The primary purpose of the program grant is to combine genetic and biochemical approaches to examine protein regulation in mammalian cells. We are particularly interested in identifying and characterizing in the mouse, genetic variants which will elucidate the regulatory mechanisms controlling (1) rates of enzyme synthesis and degradation, (2) incorporation of completed enzyme molecules into cell organelles, and (3) the timing of enzyme synthesis during development; and to apply the knowledge gained to human disease. This supplement to the original program grant seeks further support to (1) maintain our mouse colony which is developing several inbred and congenic strains, (2) study gene activation during early embryogenesis, (3) apply the technique we developed of measuring glucuronidase in a single cell to the measurement of other enzymes at the single cell level and (4) extend several of our observations or techniques to the study of human disease including the role of glucuronidase in bladder cancer and the role of aryl hydrocarbon hydroxylase in cancer of the lung, bladder, colon, and kidney.